The androgen receptor (AR) belongs to the superfamily of steroid/thyroid hormone nuclear receptors, whose other members include the estrogen receptor (ER), the progesterone receptor (PR), the glucocorticoid receptor (GR), and the mineralocorticoid receptor (MR). The AR is expressed in numerous tissues of the body and is the receptor through which the physiological, as well as the pathophysiological, effects of endogenous androgen ligands, such as testosterone (T) and dihydrotestosterone (DHT), are expressed. A compound that binds to the AR and mimics the effects of an endogenous AR ligand is referred to as an AR agonist, whereas a compound that inhibits the effects of an endogenous AR ligand is termed an AR antagonist.
The therapeutic usefulness of compounds that modulate AR, either as antagonists or as agonists, has been established by clinical studies involving a variety of disorders in both men and women. In men, drugs targeting the AR have found application in conditions related to reproductive disorders and primary or secondary male hypogonadism. A number of AR agonists, both naturally occurring and synthetic, have been clinically investigated for the treatment of musculoskeletal disorders, such as bone disease, hematopoietic disorders, neuromuscular disease, rheumatological disease, and wasting disease, as well as part of hormone replacement therapy (HRT) in cases of female androgen deficiency. In addition, AR antagonists, such as flutamide and bicalutamide, have been used to treat prostate cancer.
The beneficial effects of androgens on bone in postmenopausal osteoporosis have been documented in studies using combined testosterone and estrogen administration [Hofbauer, et al., “Androgen effects on bone metabolism: recent progress and controversies,” Eur. J. Endocrinol. 140: 271-286 (1999)]. It is also well established that androgens play an important role in bone metabolism in men, which parallels the role of estrogens in women [Anderson, et al., “Androgen supplementation in eugonadal men with osteoporosis—effects of six months of treatment on bone mineral density and cardiovascular risk factors,” Bone, 18: 171-177 (1996)]. The delitirous effects of androgen deprivation are exemplified in a study of men with stage D prostate cancer. In this study, osteopenia (50% vs. 38%) and osteoporosis (38% vs. 25%) were more conunon in men who had undergone androgen deprivation therapy (ADT) for greater than one year than the patients who had not undergone ADT [Wei, et al., “Androgen deprivation therapy for prostate cancer results in significant loss of bone density,” Urology, 54: 607-611 (1999)].
AR antagonists have also been found useful in the treatment of polycystic ovarian syndrome in postmenopausal women [see C. A. Eagleson, et al., “Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone,” J. Clin. Endocrinol. Metab., 85: 4047-4052 (2000) and E. Diamanti-Kandarakis, “The Effect of a Pure Antiandrogen Receptor Blocker, Flutamide, on the Lipid Profile in the Polycystic Ovary Syndrome,” Int. J. Endocrinol. Metab., 83: 2699-2705 (1998).] Additional uses and rationales for the development of androgen receptor modulators may be found in L. Zhi and E. Martinborough in Ann. Rep. Med. Chem. 36: 169-180 (2001). The relationship between molecular structure and the antagonistic or agonistic activity of non-steroidal AR compounds has also been the subject of numerous publications, such as J. P. Edwards, “New Nonsteroidal Androgen Receptor Modulators Based on 4-(Trifluoromethyl)-2(1H)-Pyrrolidino[3,2-g]quinolinone,” Bioorg. Med. Chem. Lett., 8: 745-750 (1998) and in L. Zhi et al., “Switching Androgen Receptor Antagonists to Agonists by Modifying C-ring Substituents on Piperidino[3,4-g]quinolinone,” Bioore. Med. Chem. Lett., 9: 1009-1012 (1999).
The established clinical usefulness makes the AR compounds highly desireable targets. A need therefore exists for chemical processes that can be used to make naturally occurring and synthetic AR-compounds. The present invention addresses this need.
These compounds are effective as androgen receptor agonists and are particularly effective as selective androgen receptor agonists (SARMs). They are therefore useful for the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration.
International application WO03/077919, published on Sep. 25, 2003, which is incorporated by reference in its entirety, describes fluorinated 4-azasteroidal derivatives that are useful in the enhancement of weakened muscle tone and the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and other hematopoietic disorders, inflammatory arthritis and joint repair, HIV-wasting, prostate cancer, benign prostatic hyperplasia (BPH), abdominal adiposity, metabolic syndrome, type II diabetes, cancer cachexia, Alzheimer's disease, muscular dystrophies, cognitive decline, sexual dysfunction, sleep apnea, depression, premature ovarian failure, and autoimmune disease, alone or in combination with other active agents.